Brain atrophy as a surrogate marker in MS

Surrogate markers that can be used as an endpoint or outcome measure in treatment trials are a major focus of experimental therapeutics and Food & Drug Administration (FDA) policy. MRI holds great promise as a surrogate measure in MS. Most existing MRI techniques assess the number or volume of white matter lesions by signal intensity. However, these measures correlate poorly with clinical measures of disability and prognosis, are labor intensive to generate, and are unreliable without careful standardization. In addition, MRI measures of white matter lesions have not yet been validated as primary outcome measures for MS clinical trials largely because changes in MR images have not met the FDA requirements for surrogacy by demonstrating that they are “reasonably likely” to predict a future clinical benefit. In this issue, Fox et al.1 report a relatively straightforward measurement of brain atrophy that promises to be a simple and robust surrogate marker for disease activity in MS.

MRI is an appealing surrogate in MS because there is increasing consensus that MRI changes reflect the pathology of the disease. Although initial studies quantified T2 signal hyperintensities, these changes include nonspecific histopathologic substrates (inflammation, edema, demyelination, gliosis) and correlate poorly with clinical measures of disability. In contrast, quantitation of gadolinium-enhanced lesions (reflecting recent blood-brain barrier disruption) assists in identifying agents that affect the acute inflammatory pathology and may predict the subsequent development of atrophy.2 Gadolinium enhancement also does not correlate well with immediate or long-term disability,3 however, and can be …